Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 year old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In this proposal we will test the hypothesis that engaging non-inflammasome dependent innate pathways by M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation. Aim 1. To examine the transcriptome signature following infection with M2SR vaccine in dendritic cells from old vs. young adults. Aim 2: To examine ex vivo efficacy of M2SR in restimulating functional anti-influenza CD8 and CD4 memory T cells in the elderly. Aim 3: To determine the adjuvants that enhance the capacity of M2SR to restimulate flu- specific memory T cells in APCs from older adults. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.